DESCRIPTION (Investigator's abstract): This effectiveness of the immune system declines with age, leaving the elderly susceptible to life-threatening diseases. This dysregulation of the aged immune system results in poor humoral responses to T-dependent antigens. Antibodies produced by aged individuals show a switch from IgG to IgM, from high affinity to low affinity, have less somatic mutations, and exhibit increased autoreactivity. This predominance of "natural immunity" is accompanied by an increase in the B-1 cell population and an impairment of memory function. The factors that produce these effects have rarely been identified and previous studies are often vague or even contradictory. The long-term goal of this proposal is to define the states in B differentiation most effected by aging. The investigator will approach aging from a novel perspective- a homogenous population of antigen-binding cells in an intact, normal host environment. When adoptively transferred into recipient mice, "quasi-monoclonal" Ig-transgenic B-cells undergo normal differentiation upon immunization. The specific aims of this proposal are 1) to determine if there are intrinsic defects in the differentiation pathway of aged B-cells, 2) to definitively determine if CD40 signaling is abnormal in aged B-cells, and 3) to determine if the aged microenvironment affects B-cell immunopoiesis. To accomplish aim 1, aged transgenic B-cells will be transferred into a young normal mouse along with young transgenic T-cells. Antigen-induced expansion, acquisition of germinal center phenotype, antibody secretion and the ability to generate memory will be measured. To accomplish aim 2, CD40 expression on naive and activated aged transgenic B-cells will be determined by flow cytometry. Proliferation and B7.2 up-regulation will be measured on cultures stimulated with anti-CD40 mAb. To accomplish aim 3, young transgenic B- and T-cells will be transferred into an aged recipient. The parameters listed in aim 1 will be measured following immunization. The results of these experiments will provide novel information on B-cell immunopoiesis and aging.